1. Field of the Invention
The present invention relates to a method for preparing racemic or optically active α-glycerophosphorylcholine, and more particularly to a method of preparing racemic or optically active D or L-α-glycerophosphorylcholine in large amounts by subjecting choline phosphate or a salt thereof and racemic or optically highly pure (S) or (R)-3-halo-1,2-propanediol to a substitution reaction in a medium at high temperature in the presence of an inorganic base which increases the activity of the reaction.
2. Description of Related Art
Racemic or optically active D or L-α-glycerophosphorylcholine, a compound represented by the following Formula 1, is known to have excellent effects on the treatment of secondary symptoms caused by cerebrovascular defects, senile cognitive disorders (memory impairment, distraction, loss of sense of direction, loss of motivation and spontaneity, concentration decline) such as degenerative brain organic psycho-syndrome, and senile pseudo-depression such as emotional and behavioral changes (emotional instability, irritability, lack of attention). In addition, this compound is known as an excellent drug that promotes the production of the brain neurotransmitter acetylcholine to thereby normalize abnormal choline neurotransmission caused by lack of acetylcholine and normalize the function of damaged neurons.
wherein * is a chiral center and refers to a racemic or optically active D or L-α-optical isomer.
The racemic or optically active D or L-α-glycerophosphorylcholine having excellent pharmacological effects as described above can be prepared by organic synthetic methods or can be prepared by deacylating the acyl phospholipids of plants (soy lecithin) or animals (egg yolk or bovine brain), and representative methods for preparation of this compound are as follows.
As shown in Reaction Scheme 1 below, Korean Patent No. 0262281 discloses a method of preparing glycerophosphorylcholine by deacylating a natural or synthetic phospholipid mixture by alcoholysis, followed by treatment with basic ion exchange resin. However, this method is a method of purifying phospholipids from a starting material containing a large amount of impurities by deacylation, and has disadvantages in that it has a low recovery of glycerophosphorylcholine in the preparation of glycerophosphorylcholine and is not suitable for the production of a large amount of glycerophosphorylcholine, due to the use of basic ion exchange resin in the purification process.
wherein R and R1 may be the same or different and are each independently a C13-C25 alkyl or a C13-C25mono- or poly-unsubstituted alkenyl.
U.S. Pat. No. 5,250,719 discloses a process of preparing D or L-α-glycerophosphorylcholine according to a method similar to that shown in Reaction Scheme 1 above. However, this process has disadvantages in that the purification process is complex due to the use of ion exchange resin and in that the recovery of L-α-glycerophosphorylcholine is low.
In European Patent No. 217,765 B1, deoleated soy or egg lecithin is deacylated, and then L-α-glycerophosphorylcholine and L-α-glycerophosphorylcholine ethanolamine are complexed with zinc salt to remove other impurities. The complex is decomposed with pyridine and separated by ion exchange resin, and the mixture of L-α-glycerophosphorylcholine and L-α-glycerophosphorylcholine ethanolamine is also separated by ion exchange resin, thereby preparing L-α-glycerophosphorylcholine. This preparation method has disadvantages in that, because the process of preparing L-α-glycerophosphorylcholine is composed of several steps, the preparation process is complex, and because the purification process comprises the use of ion exchange resin twice, it is inefficient, and also the yield is very low.
In addition, a method of preparing glycerophosphorylcholine by deacylating lecithin extracted from vegetable materials or animal organs is known (Biochim. Biophys. Acta, 488:36, 1977; Biochim. Biophys. Acta, 1003:277, 1989). However, this method has disadvantages in that, because various by-products such as D-1,2-glycerophosphate are produced depending on deacylation reaction conditions (reaction time, reaction temperature, the kind of base and the kind of solvent), the purification process is complex and the yield is low.
As seen in the above-described known examples, the methods of preparing L-α-glycerophosphorylcholine from materials such as lecithin extracted from plants or animals have an advantage in that materials required for preparation of L-α-glycerophosphorylcholine are readily available in nature. However, because the extracted material contains a large amount of impurities, it is necessary to purify the extracted material using ion exchange resin or the like, and for this reason, the purification process is complex and it is difficult to prepare L-α-glycerophosphorylcholine with high purity. In addition, because the recovery of L-α-glycerophosphorylcholine is low, the methods are uneconomical and are also unsuitable for the production of a large amount of L-α-glycerophosphorylcholine.
Meanwhile, regarding conventional methods of preparing glycerophosphorylcholine by organic synthetic methods, a method of preparing D,L-α-glycerophosphorylcholine using D,L-acetone glycerol as a stating material as shown in Reaction Scheme 2 below is known (J. Org. Chem., 26:608, 1961). However, this method has disadvantages in that, because a total of four reaction steps are carried out, the reaction process is complicated, and because the reactions are carried out under an anhydrous condition, the reaction process is complicated. In particular, there is a disadvantage in that this method is difficult to apply industrially, because the starting material D,L-acetone glycerol is very expansive and because expensive compounds such as palladium and silver carbonate are used to remove a phenyl group and a chlorine ion, which act as protecting groups in the reactions.

Furthermore, J. Am. Chem. Soc. Vol. 70. pp 1394 (1948) discloses a method of preparing L-α-glycerophosphorylcholine via a method similar to the above-described method.
As shown in Reaction Scheme 3 below, European Patent Publication No. 468100 discloses a method of preparing racemic or L-α-glycerophosphorylcholine from the substitution reaction of isopropylidene glycerol with 2-chloro-2-oxy-3,3,2-dioxaphospholane. However, this method also problems in that expansive isopropylidene glycerol and 2-chloro-2-oxy-3,3,2-dioxaphospholane are used as the starting materials and in that the reaction is carried out under an anhydrous condition, and thus the reaction conditions are strict. In addition, there is a problem in that racemic or L-α-glycerophosphorylcholine must be finally purified by ion exchange resin after hydrolysis.
wherein * is a chiral center and refers to a racemic or L-form optical isomer.
Korean Patent Application Publication No. 2011-0066004 discloses a method comprising a step of reacting a phosphorylcholine chloride calcium salt with an alkali metal base in an aqueous solution to produce an alkali metal-substituted salt, followed by a reaction with glycidol without separating the alkali metal-substituted salt.
wherein M+ represents an alkali metal such as lithium, sodium or potassium, and Cl− represents chlorine.
The preparation process shown in Reaction Scheme 4 above is a process of preparing L-α-glycerophosphorylcholine through a ring-opening reaction by reacting a phosphorylcholine chloride calcium salt with (R)-glycidol under reflux in an aqueous solution at high temperature. However, (R)-glycidol is unstable and likely to be decomposed at high temperature, resulting in an increase in the production of by-products, and for this reason, the reaction yield is low, and it is difficult to purity L-α-glycerophosphorylcholine with high purity. In addition, because of various problems, including a process of removing insoluble salts in a final step and the addition of purification by ion exchange resin for removing ions, many problems arise in preparing L-α-glycerophosphorylcholine in large amounts by the preparation process of Reaction Scheme 4.
In a method disclosed in Korean Patent Application Publication No. 2007-0119176, as shown in Reaction Scheme 5 below, phosphorylcholine chloride calcium tetrahydrate is treated with oxalic acid, sulfuric acid or EDTA in an aqueous solution to remove the calcium salt, and then as shown in Reaction Scheme 6 below, the resulting phosphorylcholine chloride is reacted with (R)-glycidol in an organic solvent, and impurities are removed therefrom by use of an organic solvent and ion exchange resin, thereby obtaining L-α-glycerophosphorylcholine.


In the preparation process shown in Reaction Schemes 5 and 6 above, there is a problem in that the calcium salt can remain depending on the pH or temperature of the reactant used in removal of the calcium salt from phosphorylcholine chloride calcium tetrahydrate so that it can interfere with a subsequent reaction to thereby reduce the yield. In addition, because the reaction with (R)-glycidol is carried out, (R)-glycidol is unstable and likely to be decomposed, resulting in an increase in the production of by-products, it is difficult to purify L-α-glycerophosphorylcholine with high purity. Furthermore, there is a problem in that the step of using the organic solvent and the ion exchange resin after completion of the reaction is complex.
In a method disclosed in Korean Patent Application Publication No. 2011-0106720, as shown in Reaction Scheme 7 below, optically active (R)-3-chloro-1,2-propanediol is reacted with a solution of a potassium hydroxide, sodium hydroxide or potassium carbonate base in distilled water in the presence of a methanol or ethanol solvent at a temperature of −10° C. to 0° C. to synthesize the intermediate (R)-glycidol, and the synthesized glycidol is subjected to a ring-opening reaction with choline phosphate or its salt at a temperature of 50° C. to 60° C., thereby preparing L-α-glycerophosphorylcholine.
wherein * is a chiral center, Y is OH or O−; and R− is a halogen atom, an anion (X−) or null.
However, in the preparation process shown in Reaction Scheme 7 above, problems may arise in that unreacted (R)-3-chloro-1,2-propanediol remains after the reaction of (R)-3-chloro-1,2-propanediol with (R)-glycidol and in that when (R)-glycidol is reacted, the production of glycerin increases with the passage of the reaction time, making it difficult to remove the glycerin. In addition, there are problems in that, because the intermediate (R)-glycidol is unstable and likely to be decomposed, resulting in an increase in the production of by-products, the reaction yield is low, and it is difficult to purify L-α-glycerophosphorylcholine. Thus, there are many problems in preparing L-α-glycerophosphorylcholine in large amounts.
Accordingly, the present inventors have made extensive efforts to overcome the above-described problems occurring in the prior art, and, as a result, have found that when choline phosphate or a salt thereof and racemic or optically highly pure (S) or (R)-3-halo-1,2-propanediol are subjected to a substitution reaction in a medium at high temperature in the presence of an inorganic base which increases the activity of the reaction, D or L-α-glycerophosphorylcholine can be prepared without a process of producing the intermediate (R)-glycidol, and also have found that D or L-α-glycerophosphorylcholine can be economically and easily prepared with high purity in high yield without having to perform a separate purification process, thereby completing the present invention.